In this proposal, we plan to elicit protective immunity to HIV-1 by activating the expression of human endogenous retrovirus (HERV) elements that encode proteins that share sufficient sequence homology to engender cross-reactive immunity. The use of normally silent endogenous genes as internal immunogens is based on recent data showing cross-reactivity between HERV and HIV-1 peptides and provocative genetic linkage between HERV loci in the human genome and control of HIV-1 virus load. Transcription from most HERV loci has been silenced by epigenetic changes to the long terminal repeat (LTR) region, and the goal of this project is to reverse this epigenetic silencing and promote the expression in lymphoid cells of two HERV transcripts, the full length HERV-K102 and pol-related HERV HCP5. Expression of these HERV-encoded proteins will stimulate an immune response that will be demonstrated to cross-react with HIV-1 antigens. Initially we will use agents known to activate latent HIV-1 LTRs to see if they will activate the selected HERV LTRs. We will then characterize the epigenetic changes and promoter binding that distinguishes latent from activated HERV LTRs. Using this knowledge, we will move to a small molecule screen of a 300,000 compound library to identify agents capable of activating HERV LTRs but not HIV-1 LTRs. The end product will be an inexpensive, orally available small molecule that will promote expression of endogenous immunogens that will provide cross-reactive immune protection against HIV-1 acquisition. The ability of this approach to elicit a cross-reactive CD8 T cell response that is protective against HIV-1 infection will be validated in vitro. The screen will also produce small molecules capable of activating HIV-1 but not HERV LTRs for use in combating latent HIV-1 infection of memory T cells, as well as small molecules capable of repressing activated HERV LTRs, providing an antidote should HERV activation have any negative impacts. This novel research proposal will take advantage of the relatedness between virus-like elements in the human genome and the HIV/AIDS virus to stimulate immunity that will prevent or slow the transmission of the HIV/AIDS virus. The approach will be to awaken the normal silent human endogenous retrovirus elements with small molecules selected from a very large library of chemical compounds, which will then provide a stimulus to the human immune system. The result will be "cross-protective" immunity, as best exemplified by the eradication of smallpox by vaccination with the related cowpox virus.